Our major goal is to understand how inactivation of the human breast cancer susceptibility gene (BRCA1) leads to breast tumorigenesis. BRCA1 ensures global genome stability through its dual participation in DNA double-strand break repair and transcriptional regulation of DNA damage-inducible genes. This proposal aims to understand how the caretaker function of BRCA1 is subserved by its role in transcription control. BRCA1 and its associated corepressor CtIP have been shown to repress transcription of the GADD45 gene that functions in G2/M cell cycle checkpoint control. Recently, we discovered ZBRK1, a novel protein, that binds to a specific DNA sequence element present in a subset of DNA damage-inducible BRCA1 target genes and represses transcription through its cognate binding site in a BRCA1- dependent manner. Based upon these preliminary observations, we hypothesize that ZBRK1, BRCA1, and CtIP coordinately repress a functionally diverse group of DNA damage-response genes in the absence of genotoxic stress. To provide support for our hypothesis, we propose the following Aims to define and characterize in molecular detail the biological role ZBRK1 as a direct link between DNA damage induced signals that converge on BRCA1 and CtIP and transcriptional control of their downstream effectors. Aim 1. is to establish the role of ZBRK1 and BRCA1 in the coordinate transcriptional regulation of functionally diverse DNA damage-response genes including GADD45 and MnSOD genes. Aim 2 is to elucidate the role of ionizing radiation (IR)-induced site-specific phosphorylation on the network of functional interactions between ZBRK1 and its associated co-repressors BRCA1 and CtIP in vivo. And Aim 3 is to establish the biological role of Ctip and Zbrk1 in response to IR in mice by germline inactivation of each corresponding gene. These studies will likely reveal novel insight into the underlying basis for the caretaker properties of BRCA1, and possibly ZBRK1 and CtIP, in preserving genomic stability and provide defined molecular targets for future intervention of breast cancer.